1. Field of the Invention
The present invention relates to 4'-demethylepipodophyllotoxin glycosides, to their use as antitumor agents, and to pharmaceutical compositions containing them.
2. Background Art
4'-Demethylepipodophyllotoxin glucosides of Formula I are antitumor agents derived from the naturally occurring lignin, podophyllotoxin II. ##STR1## The method for their synthesis is described in U.S. Pat. No. 3,524,844 to Keller-Juslen et al. Among compounds of Formula I, etoposide (Ia) and teniposide (Ib) have been established as clinically useful against a variety of tumors including small cell lung, ovarian, testicular, breast, bladder, brain, non-lymphocytic leukemia, and Hodgkin's disease.
A number of homologs, analogs and derivatives of etoposide and teniposide have been prepared and studied for antitumor activity. With few exceptions, they have been characterized by the presence of a D-glucose moiety.
Three D-galactopyranosides were reported in J. Med. Chem., 1971 (10) 936-40 and several L-glucopyranosides have been described in Chem. Lett., 1987, 799-802.
Analogs of etoposide in which one of the sugar hydroxyl groups is replaced by an amino or alkylamino group are disclosed in U.S. Pat. Nos. 4,547,567 and 4,716,221.
4'-Phosphate etoposide, a water-soluble prodrug of etoposide, is disclosed in Japan Kokai 63-192793.
Copending and commonly assigned U.S. patent application Ser. No. 240,971 describes and claims epipodophyllotoxin glucosides in which one or both of the sugar hydroxyl groups are replaced by fluorine.
4'-Demethylepipodophyllotoxin glucosides wherein the hydroxyl groups of the glucose moiety are acylated and the phenolic group is protected have been reported as intermediates for the preparation of the corresponding 4'-demethyl-epipodophyllotoxins such as compounds of Formula I.
Canadian Patent No. 956,939 discloses compounds of Formula (III) ##STR2## wherein R.sup.1 is C.sub.1-5 alkyl; R.sup.2 is acetyl or formyl; and R.sup.3 is phenyl or substituted phenyl; possible substituted phenyls mentioned but not exemplified are p-nitrophenyl and p-methoxyphenyl.
U.S. Pat. No. 4,564,675 discloses compounds of the Formula (IV) ##STR3## wherein R is --C(O)CH.sub.2 X, X is a halogen atom.
European Patent Application 162,701 discloses compounds of Formula (V) ##STR4## wherein R.sup.1 and R.sup.2 may be the same or different and each represents --C(O)CHX.sub.2 or --C(O)CX.sub.3 wherein X is a halogen atom.
Japan Kokai 58-225,096 (Derwent Abst. No. 84-0324268/06) and 58-219,196 (Derwent Abst. No. 84-027495/05) disclose compounds of Formulas (VI) and (VII), respectively. ##STR5## wherein A stands for --CO.sub.2 --CH.sub.2 --C(H).sub.m (X).sub.n wherein X is a halogen atom and m is 0 to 2 and n is 1 to 3, m+n=3 and Ac is acyl.
European Patent Application 226,202 discloses an intermediate for etoposide synthesis having the Formula (VIII) ##STR6## wherein A represents an acetyl group.
Mono-hemisuccinate derivatives of etoposide having the Formula IX are reported in J. Pharm. Biomed. Anal., 1987, 5(1): 11-20 ##STR7## wherein one of R.sup.1 and R.sup.2 is H and the other is --CO(CH.sub.2).sub.2 CO.sub.2 H. These compounds are used as a means to conjugate etoposide to bovine serum albumin.